Cannibalism and the Resistant Brain

A recent study sheds light on human resistance to prion disorders and could advance understanding of other neurodegenerative diseases such as Alzheimer and Parkinson.¹ The study focused on gene changes first identified in the Fore tribe, a formerly cannibalistic group from Papua New Guinea that experienced an epidemic of prion disease in the 1950s.

Prions are unusual transmissible proteins. They can accumulate in the brains of their victims, causing neurodegeneration and eventually death. Prion diseases include fatal conditions like Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, and mad cow disease in cattle. Because misfolded proteins and neuron death occur in prion diseases, they are used as models for more common disorders associated with misassembled protein deposits. For example, Alzheimer disease is characterized by aggregated beta-amyloid, and abnormal or overly abundant alpha synuclein deposits are a characteristic of Parkinson disease.

Studies of this isolated tribe in Papua New Guinea could help. The Fore once engaged in cannibalism as an expression of respect for the deceased. They consumed the flesh and brains of their dead loved ones, a practice that ultimately caused the spread of the neurodegenerative disease, kuru. Kuru is caused by a similar type of prion as the one that causes CJD. During the kuru epidemic in the 1950s, as many as 2% of the Fore population died each year of the disease.

The human prion protein is made up of a total of 253 amino acids. A study published in 1991² identified a prion gene variation occurring at amino acid 129 (where valine or methionine may be encoded) of the human prion protein that protects against CJD in the heterozygous MV state. Homozygotes for either amino acid (MM or VV) at position 129 do not have this resistance. In 2009, researchers, led by Professor John Collinge of University College London, found another variation among the Fore that protected against the kuru prion, at position 127.³

[[{"type":"media","view_mode":"media_crop","fid":"40117","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_3813306576677","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4069","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 160px; height: 142px; float: right;","title":"Kuru prion. © cesc_assawin/Shutterstock.com","typeof":"foaf:Image"}}]]Along with Professor Collinge, Dr. Emmanuel A. Asante of the Department of Neurodegenerative Disease, UCL Institute of Neurology and his colleagues at the MRC Prion Unit based in London are leading an effort to understand prion diseases and ultimately develop treatments for them. Based on their understanding of evidence from the 2009 study that replacing a glycine with a valine at position 127 is associated with resistance to kuru, the researchers created transgenic animals that had the same amino acid change.

In the current study,¹ the researchers created transgenic mice expressing one copy each of the wild type G127 and  the V127 variant. They injected the animals with prions and found that they were resistant to both kuru and CJD, however, they were not resistant to a different prion disease, variant CJD (the human form of bovine spongiform encephalopathy). Notably, the Fore were not exposed to this disease. Interestingly, mice that had two copies of V127 were completely resistant to all three types of prion disease.

In a press release, Asante remarked “From the human genetic work the Unit has carried out in Papua New Guinea we were expecting the mice to show some resistance to disease. However, we were surprised that the mice were completely protected from all human prion strains, the result could not have been clearer or more dramatic.”

Collinge added: “This is a striking example of Darwinian evolution in humans, the epidemic of prion disease selecting a single genetic change that provided complete protection against an invariably lethal dementia. Much work is now ongoing in the MRC Unit to understand the molecular basis of this effect which we expect to provide key insights into how this protein, and other proteins whose misfolding and polymerization is implicated in common forms of dementia, causes the disease thereby guiding us to new treatments in the years ahead.”

The study nicely illustrates the rapid evolution of resistance to human disease and also shows how one amino acid substitution can have a profound effect on protein misfolding and brain disease. Could this work pave the way for the discovery of other single gene variations that influence disease states? That is the hope of these and other researchers who are inspired by the work.

For now, Asante and his colleagues have more work to do to realize the promise of this finding. First, they need to understand more about how the protein misfolds. In additional studies, the researchers will focus on understanding the structural basis for the protection that they observed which could ultimately aid in the development of therapeutics that block aberrant protein folding. Understanding the spread of abnormal protein in prion diseases might elucidate general mechanisms of protein misfolding and genetic inheritance in common neurodegenerative conditions.

References:

1. Asante EA, et al. A naturally occurring variant of the human prion protein completely prevents prion disease. Nature. 2015;522:478-481.

2. Collinge J, et al. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet. 1991;337(8755):1441-1442.

3. Mead S, et al. A novel protective prion protein variant that colocalizes with kuru exposure. N Engl J Med. 2009;361:2056-2065.